Tracks information on drugs on worldwide basis by Dr Anthony Melvin Crasto, helping millions with websites, 9 million hits on google, 2.5 lakh connections worldwide, P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

Sunday, 6 September 2015

Toca 511 and Toca FC, developed by Tocagen, is a combination treatment currently being investigated in phase I/II trials for recurrent high grade glioma including the notoriously difficult to treat glioblastoma multiforme. Toca 511 (vocimagene amiretrorepvec) is a nonlytic retroviral replicating vector (RRV) that encodes the transgenecytosine deaminase (CD). This enzyme is used to catalyze the conversion of Toca FC, a novel oral extended-release prodrug 5-fluorocytosine (5-FC) to the active 5-fluorouracil
(5-FU). Intravenous or intracranial injection of Toca 511 takes place
during initial treatment and 3-7 weeks later the patient starts cyclic
administration of Toca FC.1,2,3 The phase I/II trials in
humans have shown similar results of patients exceeding the average life
expectancy of high grade gliomas.4
Clinical stage immuno-oncology company, Tocagen, Inc., announced the
US Food and Drug Administration has granted its primary immuno-oncology
candidate orphan drug designation as a promising and much-needed
treatment of glioblastoma, the most common form of primary brain cancer.
Every year, over 10,000 people are diagnosed with glioblastoma in the
United States. The new designation brings the company’s Toca 511 & Toca FC
closer to helping patients suffering with this type of tumor. Tocagen
is preparing to proceed with a pivotal clinical trials later this year.http://immuno-oncologynews.com/2015/08/26/tocagens-double-action-glioblastoma-treatment-receives-fda-orphan-drug-designation/ byANNA TANTRUM
Glioblastoma is known to be extremely aggressive, with newly
diagnosed patients expecting a mere five-year survival rate of less than
5 percent, along with a high likelihood of tumor recurrence despite
completion of standard treatment. Once the tumor recurs, the average
survival is only 8 months.
Toca 511 is a retroviral replicating vector (RRV) that selectively
delivers a gene for the enzyme cytosine deaminase into the tumor.
Patients then take oral cycles of Toca FC, a novel formulation of an
antifungal drug, which is converted within infected cancer cells into
the FDA-approved anticancer drug, 5-fluorouracil (5 FU). Toca 511 &
Toca FC work by programming cancer cells to convert the prodrug 5-FC
into the anticancer drug 5-FU, effectively causing tumor cell death and
stimulating the immune system through a combination of mechanisms.
“There’s an extraordinary need for new treatment options for patients with this devastating disease,” saidHarry Gruber,
M.D., chief executive officer of Tocagen. “We believe FDA’s granting of
both orphan drug and Fast Track designations to Toca 511 & Toca FC
will enable us to more efficiently advance our program, which we hope
will ultimately offer physicians and patients a new option in the fight
against brain cancer.”ImmunoCellular
Therapeutics, Ltd., announced it has come to an agreement with the US
Food and Drug Administration (FDA) on a Special Protocol Assignment
(SPA) for the Phase III registrational study of its investigational
immunotherapy, ICT-107, indicated for patients with glioblastoma.
ICT-107 is a dendritic cell-based immunotherapy targeting multiple
tumor-associated antigens on glioblastoma stem cells. The trial will be a
randomized, double-blind, placebo-controlled, and will aim to enroll
around 400 HLA-A2 positive patients. The study will be conducted across
120 sites in the US, Canada, and the European Union.

Mechanism of action

Retroviruses,
once inside the target cell, use reverse transcriptase to produce DNA
from the RNA present in the virus. Toca 511 is based on the gamma
retrovirus, murine leukemia (MLV).5
The virus has many innate properties that are suitable for targeted
cancer treatment. One of the most important properties is the
reproduction mechanism that occurs without cytolysis of the host cell.
In non-lytic reproduction, the infected cell continuously forms small
buds that are pinched off containing the virus to allow rapid infection.
Another property is the requirement for cell division. Infection is
limited to mitotically active cells. These two properties present an
ideal candidate vector for modification. The lack of cytolysis in the
host cell prevents an immune response and the necessity for the cell to
be dividing allows localization to cancerous tumors. As an oncolytic
agent, the mechanism uses the rapid mitotic activity of the cancerous
tumor cells to spread the therapeutic gene in an effective and
controlled manner.5 In Toca 511, the insertion of the CD
transgene into the active tumor catalyzes the treatment. The expression
of CD by the tumor allows intratumoral conversion of 5-FC to 5-FU.6
This allows the cytotoxic 5-FU to be maintained within the tumor cell. A
second mechanism of action is proposed based upon recent data.
Post-treatment, a systemic anticancer immune response is present that
selectively acts against the cancerous cells.4,7

Design

The design of the Toca 511 RRV is based upon the vector design by Logg et al.5
Multiple changes facilitated selection of a clinically efficacious RRV.
The original ecotropic envelope was changed to an amphotropic sequence.
In the IRES-CD cassette, multiple small repeats were removed to allow
for decreased instability during homologous recombination. A restriction
site Psi I was placed at the 3′ of IRES for the insertion of the CD
transgene. The resulting vector consists of the following, 5′ to 3′:
CMV-R-U5, PBS, 5′ SS, gag, pol (with a 3′ SS), 4070A env, IRES, Psi I, yCD2, Not I, PPT, and the U3-R-U5.8

Clinical trials

Toca 511 and Toca FC combination therapy is currently being investigated for recurrent and progressive Grade III or IV glioma.1,2,3
The initial clinical study is the first to use a RRV to facilitate gene
transfer into gliomas. In a recent presentation by Tocagen, researchers
expressed the safety and efficacy of the therapy in the first two
trials. Minimal treatment toxicity was reported. The landmark six and
twelve month survival rates were higher than previously published data
in both studies.4 Following positive results with the initial
two trials, investigation into the intravenous efficacy is currently
being determined.7

Preclinical investigations

Two important discoveries that led to the creation of Toca 511/FC
treatment are the optimization of yeast CD and modifications to the
vector backbone for genomic replication stability. The optimization of
the yeast CD involved the modification of the codon sequence at three
amino acids to a known preferred human codon sequence. This did not
change the amino acid sequence. This resulted in stability at 37°C
compared to the previous 26°C. The vector backbone modification at the env-3′ untranslated boundary created a vector with higher fidelity than the wild type.8 In studies of mice with implanted gliomas, Toca 511 and Toca FC therapy resulted in an unprecedented survival rate.6,8 Furthermore, when the mice were re-implanted with the same glioma post-treatment, memory T lymphocytes remained active and the growth was inhibited.6 The combination of these findings led to the clinical candidate that is currently undergoing trials.

MYSELF

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India.

Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker.

He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc.

He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, he has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 20 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto

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OLD BIO

DR ANTHONY MELVIN CRASTO Ph.D , Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues,

Currently he is working with GLENMARKPHARMA LTD, Research centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India.

Prior to joining Glenmark, he worked with major multinationals like Hoechst Marion Roussel, now Sanofi Aventis, & Searle India ltd, now RPG lifesciences, etc. He has worked in Basic research, Neutraceuticals, Natural products, Flavors, Fragrances, Pheromones, Vet Drugs, Drugs, formulation, GMP etc. He has total 29 yrs exp in this field, he is now helping millions, has million hits on google on all organic chemistry websites.

He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 25 year tenure, good knowledge of IPM, GMP, Regulatory aspects, he has several international drug patents published worldwide .

He suffered a paralytic stroke in dec 2007 and is bound to a wheelchair, this seems to have injected feul in him to help chemists around the world, he is more active than before and is pushing boundaries, he has one lakh connections on all networking sites, He makes himself available to all, contact him on +91 9323115463, amcrasto@gmail.com, Twitter @amcrasto